Multiple Myeloma

Multiple Myeloma is a cancer of the plasma cells. These are the blood cells responsible for producing antibodies against infectious diseases. Patients with myeloma may develop high levels of abnormal antibodies (known as "M" protein) which are non-functional. The normal antibody production is depressed in myeloma and thus patients are at increased risk of infections. Myeloma protein may also damage the kidney. As the cancerous plasma cells grow they weaken the bones, forming holes (known as ‘lytic’ lesions).

Although most patients with myeloma are over the age of 60, occasionally myeloma may strike younger individuals. Standard dose chemotherapy may control, but not cure, myeloma. Recently the use of high-dose transplantation therapy has gained popularity in this disease, as this aggressive treatment results in much longer survival.

Since the introduction of the melphalan-prednisione combination for treatment of myeloma over 30 years ago, there had been minimal improvement in overall survival rates. A recent overview of the treatment of myeloma (Gregory WM et al: Journal of Clinical Oncology 1992; 10:334) noted that although the response rates with conventional combination chemotherapy are in the range of 40-60%, fewer than 10% will achieve a complete response. The median survival for patients with myeloma, despite therapy, is only 3 years and less than 15% will remain alive at five years. Even "newer" regimens such as VMCP/VBAP and VAD have not significantly altered this median survival. Maintenance treatments, with agents such as alpha-interferon, have also not significantly improved outcomes. Although administration of the biphosphanate pamidronate (Aredia) reduces skeletal complications and improves quality-of-life issues, survival is unaffected.

Over the past decade many investigators have explored the role of high-dose treatment in this disease. In 1983 McElwain demonstrated that high-dose melphalan could overcome drug resistance in refractory myeloma. The establishment of a dose-relationship in myeloma led to trials of high-dose therapy. Multiple phase I/II trials revealed high complete response rates and suggested improved survival among newly diagnosed and relapsed patients.

Autologous Transplantation has recently become established as an effective treatment based on the results of randomized trials. A report by the Intergroupe Francais du Myelome (Attal M et al: New England Journal of Medicine 1996; 335: 91) demonstrated improved disease free survival and overall survival rates for high-dose therapy compared to standard-dose treatment. In this landmark study, 200 patients with newly diagnosed myeloma received induction standard dose therapy followed by randomization to either VMCP/VBAP or an unpurged autologous bone marrow transplant with high-dose melphalan and total body irradiation. The median event free survivals were 27 versus 18 months in favor of the transplant therapy. Similarly, the median overall survival improved from 37 months to over 5 years (not reached) with BMT. The probability of being alive at 5 years was only 12% for standard-dose therapy but was 52% with transplantation.

A pair-mate retrospective comparative trial has also favored transplantation over conventional therapy in newly diagnosed myeloma (Barlogie B et al: Blood 1997; 89:789). Results from tandem autologous transplants were compared with patients receiving standard-dose therapy. Median overall survival rates for the transplant arm was 62+ months which was statistically superior to the median survival of 46 months for conventional treatment.

The Adult Stem Cell- Bone Marrow Transplant Program of Hackensack University Medical Center has active transplant treatment protocols for Multiple Myeloma. For more information on this treatment or to schedule an appointment call (201) 996-5849.

At Hackensack University Medical Center two autologous transplantation trials for patients with myeloma are available.

As a participating ECOG transplantation center, we encourage enrollment on the US Intergroup randomized trial. This national study has undergone extensive revisions in light of the favorable French report. The protocol now represents a comparison of immediate unpurged bone peripheral blood stem cell transplantation (melphalan 140 mg/m2) with TBI following induction VAD-cyclophosphamide) versus delayed transplantation at the time of first relapse (after conventional therapy with VAD, cyclophosphamide, and VBMCP). For more information please call (201) 996- 5849

For patients choosing not to participate in the national randomized protocol, we are performing a phase II trial of high-dose melphalan 200 mg/m2 rescued by CD34 selected autologous peripheral blood stem cells. This study extends recent results from the European Bone Marrow Transplant Registry that melphalan alone may have equal efficacy with less toxicity than total body irradiation. In addition the use of CD34 stem cell selection techniques result in a 2-4 log reduction in tumor cell contamination and elimination of the human herpes virus 8 (which may be a cofactor in myeloma progression). Engraftment following blood stem cells is typically rapid (10-14 days) and has been associated with a lower complication rate than the marrow approach used in the French trial. Our transplant therapy can be administered, in part, on an outpatient basis. ). For more information please call (201) 996- 5849.

Allogeneic bone marrow transplantation for myeloma

Although the above-described autologous procedures may improve survival, these therapies are not generally felt to represent a curative approach. By contrast, allogeneic transplantation is a curative option for a variety of hematologic malignancies. Documentation of an immunologic graft-versus-myeloma effect (Tricot G et al: Blood 1996; 87:1196) and clinical remissions lasting greater than 10 years, have raised hopes for allogeneic transplantation as a potential cure. However, early experience with this approach has yielded unexpectedly high treatment related toxicities, with 1-year mortality rates approaching 40-60% in IBMTR, EBMTR, and Seattle transplantation series. Nonethesless, for the young patient (<50 years) who is willing to accept significant risks, allogeneic transplantation may offer a chance at "cure".

At Hackensack University Medical Center we are exploring three allogeneic transplant approaches in multiple myeloma.

For the young patient with an HLA-matched sibling, a traditional bone marrow transplant using high-dose melphalan with total body irradiation is available. Graft-versus-host prophylaxis consists of tacrolimus and methotrexate. For more information please call (201) 996- 5849.

For the young patient lacking an HLA-matched sibling, an unrelated bone marrow transplant using high-dose cyclophosphamide with total body irradiation is available. Graft-versus-host prophylaxis consists of tacrolimus and methotrexate. For more information please call (201) 996- 5849 or click here.

For the older patient with an HLA-matched sibling, we are attempting to exploit an adoptive immunotherapy approach. Recent data from transplantation therapy in chronic myelogenous leukemia has suggested that the graft-versus-tumor effect may represent the primary mechanism of disease irradiation. The success of donor lymphocyte infusions has led to questions regarding the need for toxic conditioning regimens and has spurred the development of non-myeloablative regimens designed to allow engraftment with less direct organ toxicity. In the older myeloma population this approach may permit the benefits of the graft-versus-myeloma effect with less early mortality. Our program is offering a conditioning regimen of low dose busulfan, anti-thymocyte globulin, and fludarabine prior to marrow infusion. For more information please call (201) 996- 5849.

In addition to the above transplantation options, the physicians at the Northern New Jersey Cancer Center are experienced in the diagnosis and treatment of this disease. Active non-transplant research studies on myeloma include:

1. A phase II trial of Interleukin-12 for plateau phase
2. A randomized trial of VAD with or without PSC-833 in refractory and relapsed disease

For more information on these protocols call (201) 996-5900.

AMYLOIDOSIS

Amyloidosis

represents a disease in which abnormal light-chain proteins (part of an antibody) are deposited within the tissues of the body. These abnormal proteins may result in heart or kidney failure, or disruption of the nerves. The survival with this disease is poor, with median survivals of only 13 months and fewer than 20% alive at 5-years.

Melphalan based therapies yield objective responses among patients with immunoglobulin deposition disease. Standard dose melphalan has increased survival to a median of 16-18 months.

Transplantation therapy is new in amyloidosis. A recent report (Comenzo Ret al: Blood 1998;91: 3662) of 25 patients noted a 68% survival rate during a median follow-up of 24 months. Two-thirds of the surviving patients had objective improvement in amyloid-related organ involvement.

The Adult Stem Cell- Bone Marrow Transplant Program of Hackensack University Medical Center has active transplant treatment protocols for Amyloidosis. . For more information on this treatment or to schedule an appointment call (201) 996-5849.

Hackensack University’s Stem Cell and Bone Marrow Transplant Program will be participating in a national ECOG trial of high-dose melphalan in amyloidosis. This study will use very high doses of the chemotherapy drug melphalan. This treatment will be rescued by autologous peripheral blood stem cells.